Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat alpha-7 nicotinic receptors.

Abstract

3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) is a selective partial agonist for rat alpha-7 nicotine receptors with reportedly much lower efficacy for human alpha-7 receptors. Because this drug improves memory-related performance in nonhuman primates, and is presently in a clinical trial for Alzheimer's disease, we investigated the potential effects of its primary human metabolite, 3-(4-hydroxy, 2-methoxy-benzylidene)anabaseine) on human as well as rat nicotinic acetylcholine receptor. 4OH-GTS-21 exhibited a similar level of efficacy for both rat and human alpha-7 receptors expressed in Xenopus oocytes. It displaced high affinity [125I]alpha-bungarotoxin binding to human SK-N-SH cell-membranes (Ki 0.17 microM) and rat PC12 cell-membranes (Ki 0.45 microM). GTS-21 also displaced [125I]alpha-bungarotoxin binding to PC12 cell membranes with high potency (Ki 0.31 microM), but was much less potent in this regard in SK-N-SH cells (23 microM). 4OH-GTS-21 produced less residual inhibition of either the human or rat AChR subtypes than GTS-21 did. To compare the neuroprotective efficacies of GTS-21 and 4OH-GTS-21 in both species, an amyloid-toxicity model (Abeta 25-35) was used. 4OH-GTS-21 was protective in both human and rat cell lines, although GTS-21 was effective only in the latter. These studies suggest that the efficacy of GTS-21 in primates may depend on a pro-drug function.

• Authors: E M Meyer, A Kuryatov, V Gerzanich, J Lindstrom, R L Papke
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 287 Issue 3 Pg. 918-25 (Dec 1998) ISSN: 0022-3565 [Print] United States
• PMID: 9864273 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 3-(4-hydroxy-2-methoxybenzylidene)anabaseine
• Benzylidene Compounds
• Bungarotoxins
• Chrna7 protein, human
• Chrna7 protein, rat
• Nicotinic Agonists
• Pyridines
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• 3-(2,4-dimethoxybenzylidene)anabaseine
• Anabasine

Topics

• Anabasine (analogs & derivatives, pharmacology)
• Animals
• Benzylidene Compounds (metabolism, pharmacology)
• Bungarotoxins (metabolism)
• Cloning, Molecular
• Dose-Response Relationship, Drug
• Humans
• Nicotinic Agonists (metabolism, pharmacology)
• Oocytes (metabolism)
• PC12 Cells
• Pyridines (metabolism, pharmacology)
• Rats
• Receptors, Nicotinic (drug effects, genetics, metabolism)
• Species Specificity
• Xenopus laevis
• alpha7 Nicotinic Acetylcholine Receptor